Novel levothyroxine formulations for oral use

ABSTRACT

The present invention relates to novel oral spray formulations of Levothyroxine. Further the invention also describes process for preparing such formulations.

BACKGROUND OF THE INVENTION

Thyroxine active drugs are known for both therapeutic and prophylactictreatment of thyroid disorders. The thyroid accomplishes its regulationfunctions by producing the hormones L-triiodothyronine (liothyronine;T3) and L-thyroxine (levothyroxine; T4). The physiological actions ofthyroid hormones are produced predominantly by T3, the majority of which(approximately 80%) is derived from T4 by deiodination in peripheraltissues.

Administration of levothyroxine sodium provides T4 to a patient. Onceabsorbed in the body, the administered T4 behaves identically to T4 thatotherwise would be secreted by the thyroid gland of the patient. Itbinds to the same serum proteins, providing a supply of circulatingT4-thyroglobulin in the patient. The administered T4 may be deiodinatedin vivo to T3. As a result, a patient receiving appropriate doses oflevothyroxine sodium will exhibit normal blood levels of T3, even whenthe patient's thyroid gland has been removed or is not functioning.

Levothyroxine sodium is prescribed for thyroid hormone replacementtherapy in cases of reduced or absent thyroid function in e.g., ailmentssuch as myxedema, cretinism and obesity. Levothyroxine sodium is quiteunstable, hygroscopic and degrades rapidly when subjected to highhumidity, light or high temperature. Because of the physicochemicalproperties of the drug, formulations of levothyroxine sodium haveextremely short shelf life.

Levothyroxine sodium is available in the form of capsules, tablets andinjection. The injection formulation is available as sterile lyophilizedproduct for parenteral administration containing 100 mcg/vial, 200mcg/vial and 500 mcg/vial.

U.S. Pat. Nos. 2,889,363 and 2,889,364 to Ginger et al., discloseprocesses for producing thyroxine sodium.

U.S. Pat. Nos. 5,955,105 and 6,056,975 to Amit et al., disclose solidpharmaceutical preparation of thyroxine drug.

U. S Pat. No. 9,006,289 to Jiang et al., discloses lyophilizedcomposition comprising of levothyroxine sodium, phosphate buffer andmannitol.

U.S. application 20140073695 to Yannis et al., discloses a method forthe preparation of an oral levothyroxine composition.

The oral formulations cannot deliver the drug into the blood at a rapidrate like the injections. On the other hand the injection formulationsare associated with painful administration to the patient. The presentinventors have developed stable oral spray formulations of Levothyroxinethat help in overcoming the disadvantages associated with the prior artformulations. These formulations may provide substantial benefitscompared to oral and other modes of drug administration, such as fasterappearance of the pharmaceutically active ingredient in the blood,improved dosage reliability, improved safety profile, increasedbioavailability and improved patient compliance. Moreover themanufacturing process time is reduced and does not require anyspecialized equipment unlike the commercially available formulations,thus making it cost efficient process.

SUMMARY OF THE INVENTION

One object of the invention provides stable oral spray formulations ofLevothyroxine and methods of preparing such formulations.

Another aspect of the invention is to provide stable oral sprayformulations comprising Levothyroxine sodium, buffering agents or pHadjusting agents, one or more solvents and other pharmaceuticallyacceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable oral spray formulation ofLevothyroxine. More particularly the invention relates to a stabilizedLevothyroxine spray formulation comprising buffering agents, solvents,and other pharmaceutically acceptable excipients.

In the context of this invention “Levothyroxine” refers topharmaceutically acceptable salts, solvates, hydrates and anhydrousforms thereof. The formulations of the present invention preferablycomprise Levothyroxine sodium.

As used herein, “oral spray formulation of Levothyroxine” refers toformulation that contains Levothyroxine in dissolved or solubilized formand is intended for oral administration. The Levothyroxine oral sprayformulation may be a clear solution designed to be sprayed directly intothe mouth, over or under the tongue.

Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidlywhen subjected to high humidity, light or high temperature. Degradationis further enhanced by the presence of water. The inventors of thepresent invention have successfully developed a stable oral liquid sprayformulation of Levothyroxine despite its rapid degrading nature.

One embodiment of the invention relates to an oral spray formulation ofLevothyroxine comprising Levothyroxine sodium and pharmaceuticallyacceptable excipients.

Another embodiment of the invention relates to oral spray formulation ofLevothyroxine comprising:

-   i. Levothyroxine-   ii. Buffering agents or pH adjusting agents-   iii. One or more solvents    and other pharmaceutically acceptable excipients.

Yet, another embodiment of the invention relates to oral sprayformulation of Levothyroxine comprising:

-   i. Levothyroxine-   ii. Buffering agents or pH adjusting agents-   iii. One or more solvents-   iv. Cyclodextrin    and other pharmaceutically acceptable excipients.

A preferred embodiment of the invention relates to oral sprayformulation of Levothyroxine comprising:

-   i. Levothyroxine sodium,-   ii. Buffering agents or pH adjusting agents-   iii. One or more solvents selected from the group comprising of,    water, polyethylene glycol, ethanol, propylene glycol and glycerol    and other pharmaceutically acceptable excipients including    cyclodextrin, sweetening agents, flavoring agents, preservatives,    penetration enhancers and stabilizers.

In a most preferred embodiment, the oral spray formulation of thepresent invention comprises:

i. Levothyroxine sodium 0.0025-5% ii. Buffering agent or pH adjustingagents 0.0015-5% iii. Solvents qs iv. Optionally other pharmaceuticallyacceptable excipients including cyclodextrin, sweetening agents,flavoring agents, preservatives, penetration enhancers and stabilizers.

Suitable buffering agents include, but not limited to phosphate,citrate, aconitic, sodium carbonate, sodium bicarbonate, tartarate,benzoate, acetate, boric acid, lactic acid, glutaric acid, malic acid,succinic acid and carbonic acid, alkali or alkaline earth salt of one ofthese acids, Tris, meglumine, amino acid buffers such as arginine,alanine, histidine, glycine, lysine and the like.

Suitable solvents include, but are not limited to dimethylacetamide(DMA), dimethyl sulfoxide (DMSO), N-Methylpyrrolidone,dimethylisosorbide, ethanol, propylene glycol, polyethylene alcohol,glycerol, propylene glycol esters, polyethylene glycols (PEG) and water.Preferred solvents are water and propylene glycol.

Suitable pH adjusting agents include the following, but are not limitedto sodium hydroxide, potassium hydroxide, ammonium carbonate,hydrochloric acid, citric acid, lactic acid, phosphoric acid andsulfuric acid. Preferred pH adjusting agents are sodium hydroxide andhydrochloric acid.

Suitable cyclodextrins include the following, but not limited to α, βand γ-cyclodextrin and cyclodextrins modified with alkyl-, hydroxyalkyl-, dialkyl-, and sulfoalkyl-ether such as methyl or hydroxypropylβ-cyclodextrins (HPCD), methyl-and-ethyl-β-cyclodextrin,sulfoalkylether-substituted beta-cyclodextrin,sulfobutylether-β-cyclodextrin (SBECD) and the like. Substitutedbeta.cyclodextrins include those substituted with one or morehydrophilic groups, such as monosaccharide (e.g., glucosyl),carboxyalkyl (e.g.,carboxymethyl, carboxyethyl),hydroxyalkyl-substituted (e.g., hydroxyethyl, 2-hydroxypropyl) and thelike. Preferably sulfobutylether-β-cyclodextrin (SBECD) is used.

The pharmaceutical formulations of the present invention may alsocontain one or more anti-oxidants and preservatives such as, but are notlimited to butylated hydroxyanisole, butylated hydroxyl toluene, citricacid, lactic acid, benzoic acid, tocopherol, monothioglycerol, ascorbicacid, L-cysteine, methyl paraben, propyl paraben, benzyl alcohol, propylgallate, thioglycolic acid, citric acid, tartaric acid, phosphoric acid,gluconic acid, thiodipropionic acid, acetonic dicarboxylic acid, sorbicacid and its salts, chelating agents and the like.

The formulation may additionally contain one or more of flavoring ortaste-masking agents and sweetening agents. Examples of taste-masking orflavoring agents include, but are not limited to, synthetic or naturalpeppermint oil, spearmint oil, citrus oil, fruit flavors (e.g., citrus,orange, lemon, strawberry, melon and mixtures) and sweeteners (e.g.,sugars, sorbitol, mannitol, dextrose, sucrose, fructose, levulose,aspartame, sodium cyclamate, saccharin, and sucralose).

The formulation may also contain absorption enhancers or penetrationenhancers such as, but not limited to surfactants such as sodium laurylsulfate, sodium dodecyl sulfate, dioctyl sodium sulfosuccinate, tweens,polysorbates, cetylpyridinium chloride, chitosan, trimethyl chitosan,poly-L-arginine and L-lysine; fatty acids and derivatives; bile salts,chelating agents, sulfoxides such as dimethyl sulfoxide (DMSO),decylmethyl sulfoxide; polyols and alcohols.

Optionally stabilizing agents, solubility enhancers and viscositymodifying agents may also be added.

The oral spray formulation can be packed into any suitable containers.Preferred containers are pharmaceutically acceptable glass,polyethyleneterephthalate (PET), high density polyethylene (HDPE),crystal zenith (CZ), polyolefins like polypropylene (PP) or polyethylene(PE), cyclic olefins polymer (COP), cyclic olefin copolymer (COC)bottles, pfeiffer pumps or within any type of pharmaceuticallyacceptable package, container, pump or bottle.

Comparative dissolution study was performed with Levothyroxine sodiumformulation prepared according to the invention and commerciallyavailable Levothyroxine sodium tablets (AEB1997, Thyronorm 150 mcg).Dissolution study was performed in 500 ml of 0.01N HCl+0.2% SLS (sodiumlauryl sulphate) dissolution media at 50 RPM. Comparative dissolutionprofiles were recorded and tabulated in table 1.

TABLE 1 Comparative dissolution profile Product Reference productInvention formulation Strength 150 mcg (Tablet) 250 mcg (Oral solution)% Dissolution 45 Min 67 95

The following examples further describe certain specific aspects andembodiments of the present invention and demonstrate the practice andadvantages thereof. It is to be understood that the examples are givenby way of illustration only and are not intended to limit the scope ofthe invention in any manner.

EXAMPLES Example 1

S.No Ingredients Quantity 1 Levothyroxine sodium 0.01-1 mg 2 Arginine0.01-4 mg 3 Propylene glycol 0.01-1 ml 4 Sodium hydroxide q. s 5Ultrapure water q.s to 0.1-2 ml

Manufacturing Process

Ultrapure water was taken in a compounding vessel and arginine was addedand stirred. Propylene glycol was added to the solution and stirred. pHof the solution was adjusted to 11±0.5 by the addition of sodiumhydroxide solution. Then the bulk solution was cooled to 2° C. to 8° C.Levothyroxine sodium was added and stirred till a clear solution wasobtained, while maintaining the temperature at 5±3 ° C. The solution wasfiltered, followed by filling into suitable containers.

Example 2

S.No Ingredients Quantity 1 Levothyroxine sodium 0.01-1 mg 2 Alanine0.006-4 mg 3 Propylene glycol 0.01-1 ml 4 Sodium hydroxide q. s 5Ultrapure water q.s to 0.1-2 ml

Manufacturing Process

Ultrapure water was taken in a compounding vessel and alanine was addedand stirred. Propylene glycol was added to the solution and stirred. pHof the solution was adjusted to 11±0.5 by the addition of sodiumhydroxide solution. Then the bulk solution was cooled to 2° C. to 8° C.Levothyroxine sodium was added and stirred till a clear solution wasobtained, while maintaining the temperature at 5±3° C. The solution wasfiltered, followed by filling into suitable containers.

Example 3

Quantities in mg S.No Ingredients F1 F2 F3 F4 1 Levothyroxine sodium 0.50.5 0.5 0.5 2 Mannitol 3 — — — 3 Dibasic sodium phosphate 0.5 — — —heptahydrate 4 Arginine — 15 — — 5 Alanine — — 6 — 6 Glycine — — — 15 7Sodium hydroxide q.s to adjust the pH 11.0 ± 1.0 8 Ultrapure water q.sto 1 ml

Manufacturing Process

Ultrapure water was taken in a compounding vessel and buffering agent(as mentioned in example 3) was added and stirred. Mannitol was added ifnecessary (F1). pH of the solution was adjusted to 11±1.0 by theaddition of sodium hydroxide solution. Then the bulk solution was cooledto 2° C. to 8° C. Levothyroxine sodium was added and stirred till aclear solution was obtained, while maintaining the temperature at 5±3°C. The solution was filtered, followed by filling into suitablecontainers.

Levothyroxine formulations prepared according to example 3, were testedfor stability at 25±2° C./60±5% RH (1 week); 40±2° C./75±5% RH (1 week)and 60±2° C. (3 days). The data is summarized in table 2.

TABLE 2 Stability of the formulation Stability Data F1 F2 F3 F4 Assay 25± 2° C./60 ± 5% RH (1 wk) 98.1 100.5 98.4 94.5 40 ± 2° C./75 ± 5% RH (1wk) 95.6 100.5 98.6 93.4 60 ± 2° C. (3 days) 89.8 99.5 87.3 90 TotalImpurities 25 ± 2° C./60 ± 5% RH (1 wk) 1.06 0.25 0.42 0.44 40 ± 2°C./75 ± 5% RH (1 wk) 1.73 0.39 0.34 0.63 60 ± 2° C. (3 days) 4.75 1.061.43 3.45

Example 4

S.No Ingredients Quantity per mL 1 Levothyroxine sodium 0.01-1 mg 2L-Arginine 0.01-4 mg 3 Propylene glycol 0.02 mL-0.4 mL 4 Methyl paraben0.5-1.5 mg 5 Sodium hydroxide q.s 6 Ultrapure water qs to 0.1-2 ml

Manufacturing Process

Ultrapure water was taken in a compounding vessel and L-Arginine wasadded and stirred. Propylene glycol was added to the solution andstirred. Methyl paraben was added. pH of the solution was adjusted to11±0.5 by the addition of sodium hydroxide solution. The solution wascooled to 2° C. to 8° C. Levothyroxine sodium was added and stirred tilla clear solution was obtained. The solution was filtered, followed byfilling into suitable containers.

Example 5

S.No Ingredients Quantity per mL 1 Levothyroxine sodium 0.01-1 mg 2L-Arginine 0.01-4 mg 3 Propylene glycol 0.02 mL-0.4 mL 4 Propyl paraben0.05-0.5 mg 5 Sorbitol 0.5-1.5 mg 6 Sodium hydroxide q.s 7 Ultrapurewater q.s to 1.0 mL

Manufacturing Process

Ultrapure water was taken in a compounding vessel and L-Arginine wasadded and stirred. Propylene glycol was added to the solution andstirred. Propyl paraben was added. Sorbitol was added to the solutionand stirred. pH of the solution was adjusted to 11±0.5 by the additionof sodium hydroxide solution. The solution was cooled to 2° C. to 8° C.Levothyroxine sodium was added and stirred till a clear solution wasobtained. The solution was filtered, followed by filling into suitablecontainers.

Example 6

Quantity per mL Quantity per mL S.No Ingredients (A1) (A2) 1Levothyroxine sodium 0.01-2 mg 0.01-2 mg 2 Arginine 0.01-4 mg 0.01-4 mg3 SBECD 100-400 100-400 4 Potassium sorbate — 2-6 mg 5 Sodium iodide0.5-4.0 0.5-4.0 6 Ultrapure water q.s to 1.0 mL q.s to 1.0 mL

Manufacturing Process

Ultrapure water was taken in a compounding vessel and SBECD,levothyroxine, Arginine, potassium sorbate and sodium iodide were addedand stirred. pH of the solution was adjusted to 6±0.5 with sodiumhydroxide or hydrochloric acid. The solution was filtered, followed byfilling into suitable containers.

Levothyroxine formulations prepared according to example 6, were testedfor stability at 2-8° C., 25±2° C./60±5% RH and 40±2° C./75±5% RH for aperiod of 3 months. The data is summarized in table 3.

TABLE 3 Stability of the formulation Stability data A1 A2 Stabilityduration 1M 3M 1M 3M Assay 2-8° C. 98.3 97.3 100.9 100.3 25 ± 2° C./60 ±5% RH 98.3 97.2 98.9 100.1 40 ± 2° C./75 ± 5% RH 97.9 97.1 100.5 99.8Total Impurities 2-8° C. 0.62 0.88 0.66 0.95 25 ± 2° C./60 ± 5% RH 0.620.92 0.73 0.95 40 ± 2° C./75 ± 5% RH 0.72 1.16 0.87 1.29

We claim:
 1. An oral spray formulation of Levothyroxine comprisingLevothyroxine sodium and pharmaceutically acceptable excipients.
 2. Theformulation of claim 1 comprising : (i) Levothyroxine sodium (ii)Buffering agents or pH adjusting agents (iii) One or more solvents (iv)Optionally one or more pharmaceutically acceptable excipients
 3. Theformulation of claim 2 comprising: (i) Levothyroxine sodium 0.0025-5%(ii) Buffering agents or pH adjusting agents 0.0015-5% (iii) Solvents qs(iv) Optionally one or more pharmaceutically acceptable excipients.


4. The formulation of claim 1 comprising : (i) Levothyroxine sodium (ii)Buffering agents or pH adjusting agents (iii) One or more solvents (iv)Cyclodextrin (v) Optionally one or more pharmaceutically acceptableexcipients
 5. An oral spray formulation of Levothyroxine according toclaims 2 and 4, wherein the buffering agents are selected fromphosphate, citrate, sodium carbonate, sodium bicarbonate, tartarate,benzoate, lactate, acetate, glutaric, malic, succinic and carbonic acid,Tris, meglumine, amino acid buffers such as arginine, alanine,histidine, glycine and lysine.
 6. An oral spray formulation ofLevothyroxine according to claims 2 and 4, wherein the pH adjustingagents are selected from sodium hydroxide, potassium hydroxide, ammoniumcarbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acidand sulfuric acid.
 7. An oral spray formulation of Levothyroxineaccording to claims 2 and 4, wherein solvents are selected from ethanol,propylene glycol, glycerol, polyethylene glycols (PEG) and water.
 8. Anoral spray formulation of Levothyroxine according to claim 1, whereinthe pharmaceutically acceptable excipients are selected from the groupcomprising cyclodextrins, sweetening agents, flavoring agents,preservatives, penetration enhancers and stabilizers.
 9. An oral sprayformulation of Levothyroxine according to claim 8, wherein thecyclodextrin is selected from α, β and γ-cyclodextrin and cyclodextrinsmodified with alkyl-, hydroxyalkyl-, dialkyl-, and sulfoalkyl-ether suchas methyl or hydroxypropyl β-cyclodextrins (HβCD),sulfoalkylether-substituted beta-cyclodextrin,sulfobutylether-β-cyclodextrin (SBECD).